The population of peripheral blood CD3+ T cells include a minor population that uses the 78 T cell receptor. 78 T cells arise by thymic or extrathymic pathways, recognize nonpeptidic antigens in an MHC-unrestricted manner, and are components of innate immunity. 78 T cells constitute 3-6 percent of healthy blood T cells, of which >70 percent express the Vy2/V82 chains. Within the V72 repertoire, most chains also contain the J71.2 segment. Central to this proposal is the observation that V72-JT1.2/V82 T cells are depleted preferentially during untreated HIV infection; the effect is specific and spares cells expressing other V72-J combinations or cells expressing other 78 T cell receptors. Prolonged antiretroviral therapy (up to 3 years) partly restores the V72-JT1.2 repertoire. Studies proposed in this application will extend the characterization of V72 repertoire changes during HIV infection, to establish valid associations between the presence of JT1.2 segments and the restoration of host immunity against HIV-1. The effectiveness of antiretroviral therapy is judged by the ability to maintain low virus levels in plasma, to restore CD4 cell counts, and to restore T cell proliferation, CTL activity, and antibody titers to viral antigens. We hypothesize that restoration of 78 T cell repertoire and function, will occur in parallel with changes in the acquired immune response and both will reflect a positive benefit of therapy. The evaluation of 78 T cells, with focus on the V72 repertoire, provides a simple, quantitative method for assessing immune restoration, and could be an important tool for assessing therapeutic benefit. In addition, depletion of 78 T cells is a model for indirect consequences of HIV infection, where cells are depleted or altered despite not being susceptible targets for infection. Our preliminary data identified a potential role for interferon-alpha and activation-induced cell death in mechanisms for 78 T cell depletion. We will pursue these mechanistic studies to increase our understanding of clinical situations that favor depletion or restoration. Few therapies have targeted innate immunity, due to a lack of understanding about regulation of these mechanisms and a lack of data directly relating to AIDS pathogenesis. Our studies test the relationships of 78 T cell innate immunity to HIV disease, and may evolve new surrogate markers for evaluating immune restoration during therapy for AIDS.